Activated macrophages exhibit a wide range of activities, including the presentation of antigen, the recruitment of inflammatory cells, the stimulation of cell growth, and the destruction of pathogens and tumor cells. Cytokines play a central role in macrophage physiology, both as macrophage activators (Adams, (1989) Immunol. Today 10:33-35) and as mediators of macrophage activities (Nathan, (1987) J. Clin. Invest. 79:319-326). The best characterized macrophage-activating cytokine is .gamma.-interferon (IFN-.gamma.), which is able to induce the expression of major histocompatibility complex class II antigens (Rosa, et al. (1983) EMBO J. 2:1585-1589), prime macrophages for the release of reactive oxygen intermediates that are important for pathogen and tumor cell killing (Nathan, et al. (1984) J. Exp. Med. 160:600-605), and enhance the expression of the pleiotropic macrophage products tumor necrosis factor (TNF) and interleukin 1 (IL-1) (Collart, et al. (1986), J. Exp. Med. 164:2113-2118.
IFN-.gamma.(type II IFN) and other macrophage activators such as lipopolysaccharide (LPS) and type I IFN (IFN-.alpha. and IFN-.beta.) act by altering gene expression (Revel, et al. (1986) Trends Biochem. Sci. 11:166-170; Tannenbaum, et al. (1988), J. Immunol. 140:3640-3645)). While the sets of genes induced by these factors overlap, genes have been identified that are activated preferentially by type II IFN (Luster, et al., (1985) Nature 315:672-676; Fan, et al., (1989) Mol. Cell. Biol. 9:1922-1928) or by type I IFN (Revel, et al. supra) or by LPS (Tannebaum, et al., supra). As regards the IFNs, the molecular mechanisms whereby genes are differentially regulated by type I and type II IFNs are unknown.
The cytokines produced by activated macrophages include, in addition to extensively studied mediators such as TNF and IL-1, secreted proteins such as the members of the platelet factor 4 (PF4) family, including IP-10 (Luster, et al., (1985) Nature 315:672-676), IL-8 (Matsushima, et al. (1988), J. Exp. Med. 167:1883-1893), and macrophage inflammatory protein 2 (MIP-2) (Wolpe, et al., (1989) Proc. Natl. Acad. Sci., USA 86:612-1893). Both IL-8 and MIP-2 have been shown to be chemoattractants for human neutrophils, and IL-8 has been found to modulate neutrophil adherence to endothelial cells (Gimbrone, et al. (1989) Science 246:1601-1603).
It is presumed that there are as yet undiscovered macrophage products that function as mediators for some of the activities of activated macrophages. There is a need in the art to know how activated macrophages exert their effects and to identify and isolate the factors which mediate macrophage activities.